Impact of multidrug resistance on outcomes in hematologic cancer patients with bacterial bloodstream infections

Despite the improved outcomes in patients with hematological malignancies, infections caused by multidrug-resistant organisms (MDROs) pose a new threat to these patients. We retrospectively reviewed the patients with hematological cancer and bacterial bloodstream infections (BSIs) at a tertiary hospital between 2003 and 2022 to assess the impact of MDROs on outcomes. Among 328 BSIs, 81 (24.7%) were caused by MDROs. MDRO rates increased from 10.3% (2003–2007) to 39.7% (2018–2022) (P < 0.001). The 30-day mortality rate was 25.0%, which was significantly higher in MDRO-infected patients than in non-MDRO-infected patients (48.1 vs. 17.4%; P < 0.001). The observed trend was more pronounced in patients with newly diagnosed diseases and relapsed/refractory disease but less prominent in patients in complete remission. Among MDROs, carbapenem-resistant Gram-negative bacteria exhibited the highest mortality, followed by vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and extended-spectrum β-lactamase-producing Enterobacteriaceae. Multivariate analysis identified independent risk factors for 30-day mortality as age ≥ 65 years, newly diagnosed disease, relapsed/refractory disease, MDROs, polymicrobial infection, CRP ≥ 20 mg/L, and inappropriate initial antibiotic therapy. In conclusion, MDROs contribute to adverse outcomes in patients with hematological cancer and bacterial BSIs, with effects varying based on the underlying disease status and causative pathogens. Appropriate initial antibiotic therapy may improve patient outcomes.


Study patients
Bacterial BSI was defined as the presence of bacterial growth in blood cultures.Clinical and microbiological assessments were performed to determine the etiological significance of the isolated pathogens.Coagulase-negative staphylococci, Bacillus spp., Corynebacterium spp., and Cutibacterium acnes were considered contaminants unless they were isolated from two or more separate blood culture sets.Polymicrobial BSI was defined as the detection of two or more different bacterial organisms on the first day of a BSI episode.When a patient experienced more than one episode of bacterial BSI during each admission, only the first episode for each admission was considered to avoid non-independence associated with repeated measures.

Definitions
In several previous studies, MDROs were defined as bacteria showing resistance to at least one agent in three or more antibiotic classes 8,11,13 .However, because of inconsistencies in the antimicrobials included in the automated susceptibility test panels in our hospital over the 20-year study period, MDROs were composed of typical highly resistant organisms, including MRSA, VRE, ESBL-producing Enterobacteriaceae, and carbapenemresistant GNB 9 .Carbapenem-resistant GNB were defined as Enterobactericae, Pseudomonas aeruginosa, and Acinetobacter species that exhibit non-susceptibility to at least one of three carbapenem antibiotics (imipenem, meropenem, and doripenem).Stenotrophomonas maltophilia, which is intrinsically resistant to carbapenem antibiotics, was also classified as carbapenem-resistant GNB 14 .The susceptibility of bacteria to antibiotics was determined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) 14 .The susceptibility breakpoints for imipenem, meropenem, and doripenem in Enterobacteriaceae were revised from ≤ 4 to ≤ 1 mg/L in 2010.For Pseudomonas aeruginosa, the susceptibility breakpoints were revised from ≤ 4 to ≤ 2 mg/L in 2012.Similarly, the susceptibility breakpoints for Acinetobacter species were revised from ≤ 4 to ≤ 2 mg/L in 2014 14,15 .To quantify the overall comorbidity burden, we calculated Charlson Comorbidity Index scores using codes from the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) 16,17 .The initial antibiotic therapy administered within the first 72 h was categorized as appropriate or inappropriate, depending on the results of antibiotic susceptibility testing 18 .

Statistical analyses
Chi-square or Fisher's exact tests were used to compare categorical variables between the two groups, as appropriate.Student's t-test and Mann-Whitney U test were used for continuous variables with normal and non-normal distributions, respectively.The normality of the distribution was assessed using the Shapiro-Wilk test.We used a linear-by-linear association test for ordinal data.Univariate and multivariate logistic regression analyses were performed to identify independent factors associated with 30-day mortality.A multivariate logistic regression model included all significant variables (P ≤ 0.05) following the univariate analysis.Continuous variables that were significant predictors in the univariate analysis were dichotomized using cut-off values derived from the classification and regression tree 19 .These dichotomized variables were then included in the multivariate model.Survival was determined using the Kaplan-Meier method, and the survival curves of the two groups were compared using the log-rank test.All statistical tests were two-tailed, and a P value ≤ 0.05 was considered statistically significant.All analyses were performed using R statistical software (version 4.3.2;R Foundation for Statistical Computing, Vienna, Austria).

Ethical approval and Informed consent
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.The Institutional Review Board of the Kyung Hee University Hospital approved this study (approval number 2023-06-068), and given its retrospective nature, written informed consent was waived.

Discussion
This study assessed trends in the prevalence of MDROs and their impact on outcomes in 328 hematological patients with bacterial BSIs.Over the 20-year study period, the rates of MDROs in bacterial BSIs within the population increased significantly by fourfold, affecting both Gram-positive and GNB.This substantial increase in MDR rates was also well-documented in a recent study involving 552 patients with hematological malignancies 10 .This study demonstrated that carbapenem resistance and MDR rates increased from 0 to 40% in Pseudomonas species and from 17 to 82% in Acinetobacter baumannii 10 .
In this study, the two notable factors for mortality in patients with hematologic cancer and bacterial BSIs were disease status and MDROs.We observed a higher mortality rate in patients with a newly diagnosed or refractory www.nature.com/scientificreports/disease than in those in remission (Table 3).This increased mortality in patients in non-remission may be due to immunosuppression resulting from a higher disease burden.After adjusting for disease status, we found that MDROs were independently associated with a threefold increase in the odds of mortality (Table 3).The adverse effect of MDROs on patient outcomes was more pronounced in patients who were not in remission, with a mortality rate exceeding 60%, as opposed to 17% in those in remission (Fig. 3).Consistent with our findings, Scheich et al. found that the overall survival of hematological bacteremia patients infected with Gram-negative MDR bacteria was significantly lower than that of patients infected with Gram-negative non-MDR bacteria (85.6 vs. 55.9%) 11.However, they did not find a significant association between the disease status and outcomes, potentially because of the small number of patients in remission (only three) 11 .In patients with hematological cancer, MDRO colonization is associated with subsequent bacterial BSIs 7,13 .Based on these findings and our data, we suggest that stringent infection control measures are critical in patients with hematological cancer to prevent MDRO colonization and subsequent BSI.
We assessed the effects of various pathogens on the patient outcomes (Fig. 5).Carbapenem-resistant GNB had the most adverse outcomes, whereas streptococci, coagulase-negative staphylococci, and non-ESBL-producing Enterobacteriaceae were associated with better outcomes.This finding aligns with recent observations by Weber et al., who analyzed 637 bacterial BSI episodes in patients with predominantly hematological malignancies 20 .Carbapenem-resistant GNB exhibited the highest mortality rate (62%), with a 5.6-fold increase in the odds of mortality in our study, consistent with the 9.5-fold increase in the hazard ratio for mortality reported by Weber et al. 20 .Notably, the CRE rate in this study was only 1.2%.Most carbapenem-resistant GNB were non-fermenting GNB, such as A. bauamanni, P. aeruginosa, and S. maltophilia (Table 1).Non-fermenting GNB are intrinsically resistant to many antimicrobials and can acquire resistance to any antimicrobial agents 8,14 .Bacterial BSIs caused by these organisms result in high mortality rates, ranging from 23 to 65% among patients with hematological cancer [21][22][23] .In a study by Scheich et al., patients with hematological bacteremia infected with MDR non-fermentators had worse overall survival than those infected with non-MDR non-fermentators (71 vs. 31%) 11 .VRE bacteremia resulted in a mortality rate of 50%, with a 3.2-fold increase in the odds of mortality compared to non-VRE bacteremia in our study, consistent with the 2.1-fold increase in the hazard ratio for mortality reported by Weber et al. 20 .Among patients undergoing hematopoietic cell transplantation, those with VRE BSI had a 4.7fold increased risk of 1-year non-relapse mortality compared with patients without BSI 24 .The negative impact of polymicrobial BSIs in our patients is consistent with the findings of previous studies 5,7 .
Appropriate selection of empiric therapy is critical in hematologic patients at high risk of MDRO infection.In this study, a three-fold higher rate of inappropriate initial antibiotic therapy was observed in bacterial BSIs caused by MDROs than in those caused by non-MDROs (42 vs. 14%, respectively) (Table 2).We found that inappropriate initial therapy was independently associated with a 2.4-fold increase in the odds of mortality (Table 3).Our data are consistent with those of a study documenting the same association in patients with hematological malignancies and Gram-negative bacterial BSIs 18 .We observed that AML and more extended hospital stays were risk factors for MDROs (Table 1 and Fig. 2).In a previous study, 155 (50%) of 312 patients with AML were colonized with MDROs before, during, or after their hospital stay after induction chemotherapy 25 .The high rates of MDRO colonization in patients with AML may be attributed to prolonged hospital stays stemming from significant bone marrow suppression after chemotherapy.In our study, patients with AML had the most prolonged duration of hospitalization compared to those with other diseases.Therefore, in patients with AML or a prolonged length of stay, empiric antibiotic therapy against MDROs should be considered for suspected bacterial BSIs.However, it cannot be emphasized enough that the initial broad-spectrum antibiotic coverage for MDRO infections should be modified based on the final blood culture results.
The main limitation of this study was its retrospective nature, which could lead to potential missing or inaccurate data collection.However, we attempted to mitigate this issue by using a standardized data form for detailed clinical data collection and involving three authors (K.H. P., Y. J. J., and J. J. H.) in the data review.Disagreements Figure 3.Comparison of 30-day mortality between patients infected with multidrug-resistant organisms (MDROs) and those infected with non-MDROs according to disease status.Among patients newly diagnosed with malignancy or experiencing relapsed/refractory disease, the mortality rate was higher in the MDROs group compared to the non-MDROs group.However, this difference was not observed in patients who were in complete remission.among the authors were resolved through regular meetings.To ensure accurate identification of comorbid illnesses, we utilized both chart review and ICD-10 codes.Additionally, because the study was conducted at a single center, the generalizability of the findings to other settings with different patient populations or microbiological pathogens may be limited.Finally, the relatively small sample size compromised the statistical power of the study, potentially hindering the detection of differences within subgroups.
In conclusion, hematological patients with MDR bacterial BSI had a higher mortality rate than those with non-MDR bacterial BSI.The effect of MDROs on mortality varied considerably according to the type of disease status and causative pathogens but was independent of the type of hematological malignancy.Our findings

Figure 2 .
Figure2.The multidrug resistance (MDR) rates according to length of hospital stay.A significant trend was observed, showing an increase in MDR rates with more extended hospital stays.The P-value was calculated using the linear-by-linear association test.

Figure 4 .
Figure 4. Kaplan-Meier analysis demonstrated a higher mortality rate among patients infected with multidrugresistant organisms (MDROs) compared to those infected with non-MDROs (A).Similar trends were observed in patients infected with Gram-positive MDROs (B) and Gram-negative MDROs (C).Patients who received inappropriate empirical therapy exhibited a higher mortality rate compared to those who received appropriate empirical therapy (D).

Table 2 .
Baseline characteristics and outcomes of 328 patients with hematological cancer with bacteremia caused by multidrug-resistant organisms (MDROs) and non-MDROs.The data are presented as no.(%) of patients or median (interquartile range), unless otherwise indicated.ANC, absolute neutrophil count; ICU, intensive care unit; LOS, length of stay; MBI-LCBI, mucosal barrier injury laboratory-confirmed bloodstream infection; WBC, white blood cell.

Table 3 .
Univariate and multivariate regression analyses of risk factors for 30-day mortality in 328 patients with hematological cancer and bacterial BSIs.The data are presented as no.